key: cord-1003138-8qujes7q
authors: Jutzeler, Catherine R.; Bourguignon, Lucie; Weis, Caroline V.; Tong, Bobo; Wong, Cyrus; Rieck, Bastian; Pargger, Hans; Tschudin-Sutter, Sarah; Egli, Adrin; Borgwardt, Karsten; Walter, Matthias
title: Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: A systematic review and meta-analysis
date: 2020-08-04
journal: Travel Med Infect Dis
DOI: 10.1016/j.tmaid.2020.101825
sha: 18b6e832d861acc5faf925232ea60fe37f872569
doc_id: 1003138
cord_uid: 8qujes7q

INTRODUCTION: Since December 2019, a novel coronavirus (SARS-CoV-2) has triggered a world-wide pandemic with an enormous medical and societal-economic toll. Thus, our aim was to gather all available information regarding comorbidities, clinical signs and symptoms, outcomes, laboratory findings, imaging features, and treatments in patients with coronavirus disease 2019 (COVID-19). METHODS: EMBASE, PubMed/Medline, Scopus, and Web of Science were searched for studies published in any language between December 1(st), 2019 and March 28(th). Original studies were included if the exposure of interest was an infection with SARS-CoV-2 or confirmed COVID-19. The primary outcome was the risk ratio of comorbidities, clinical signs and symptoms, imaging features, treatments, outcomes, and complications associated with COVID-19 morbidity and mortality. We performed random-effects pairwise meta-analyses for proportions and relative risks, I(2), Tau(2), and Cochrane Q, sensitivity analyses, and assessed publication bias. RESULTS: 148 studies met the inclusion criteria for the systematic review and meta-analysis with 12’149 patients (5’739 female) and a median age of 47.0 [35.0-64.6] years. 617 patients died from COVID-19 and its complication. 297 patients were reported as asymptomatic. Older age (SMD: 1.25 [0.78- 1.72]; p < 0.001), being male (RR = 1.32 [1.13-1.54], p = 0.005) and pre-existing comorbidity (RR = 1.69 [1.48-1.94]; p < 0.001) were identified as risk factors of in-hospital mortality. The heterogeneity between studies varied substantially (I(2); range: 1.5-98.2%). Publication bias was only found in eight studies (Egger’s test: p < 0.05). CONCLUSIONS: Our meta-analyses revealed important risk factors that are associated with severity and mortality of COVID-19.

With the exception of one 10-month old child, all deaths were non-pregnant adult COVID-19 patients.

Higher proportions of male than female patients were reported to be infected with SARS-CoV-2 (t = 2.678, df = 202, p-value = 0.008; Figure 2A ) across all studies. Comorbidities were present in ~31% of the adult patients (2'329/ 7'608), with hypertension being the most prevalent one (1'352/ 6'460 patients, 20 .93%), followed by heart failure (37/ 354 patients, 10 .5%), diabetes mellitus (678/ 6'535 patients, 10 .4%), and coronary heart disease (194/ 2'388 patients, 8 .5%) ( Figure 4A , Table 4 Table 4 . As shown in Figure 4D , the most common treatments were antivirals (4'475/ 6'068, patients, 73.8%), oxygen therapy (1'300/ 1'872 patients, 69 .4%), and antibiotics (2'518/ 4'825 patients, 52.2%). Detailed information on all treatments is provided in in Table 4 . Eight percent (616/ 7'727 patients) of the adults died during the hospitalization due to complications related to Amongst the survivors (7'111/ 7'727 patients, 92.0%), a total of 3'025 (68.7%) remained hospitalized, 1'751 (32.4%) were discharged, and 1'012 (27.1%) reportedly recovered ( Figure 4C , Table 4 ). Important to note, for some patients it was stated that they both, recovered and were discharged (i.e., one patient can fall in multiple categories). The median duration between symptoms onset and hospitalization was 8 days [7 -9.5] . A total of 195 (6.8%) patients were admitted to the intensive care unit (ICU). The most frequently reported complications associated with COVID-19 were pneumonia (1'032/ 1'489 patients, 69 .2%), respiratory failure (141/ 413 patients, 34 .1%), acute cardiac injury (242/ 1'250 patients, 19 .4%), and ARDS (759/ 5'122 patients, 14 .8%), ( Figure  4D , Table  4 ).

Studies investigating the effect of COVID-19 in pregnant women reported that only five pregnant women had any history of comorbidities. Hypothyroidism, allergies, or influenza were reported each for one pregnant woman (Supplementary Table 5 Table 4 . Moreover, antibiotics (14/ 14 patients, 100.0%), antivirals (11/ 14 patients, 78.6%) and oxygen therapy (high flow nasal cannula; 3/ 12 patients, 25 .0%) were used to treat pregnant COVID-19 patients (Supplementary Table 5 ). None of the pregnant COVID-19 patients died.

Lastly, one patient was admitted to the ICU (Supplementary Table 5 ).

Similar to the adult cohort, the proportion between female and male patients were comparable in the pediatric/neonatal cohort (t = 1.169, df = 26, p-value = 0.253; Figure 2B ). Fourteen percent of the children and neonates were asymptomatic (149/ 1'054). With the exception of two children, no comorbidities were reported for any of the pediatric or neonatal patients (Supplementary Table 6 ). Table 6 ).

Twelve studies (2'596 patients) provided separate data for patients with a severe (500 patients, 19 .3%) and non-severe disease status (2'096, 80.7%). No differences regarding sex were found between severe Table 5 ) were associated with worse outcome (i.e., severe disease). To test if the increased risk of heart conditions is attributable to the study that has classified their patients into severe and non-severe based on the presence or absence of cardiac injuries, we conducted a sensitivity analysis excluding these studies 44 .

The risk of any heart condition remained significantly elevated in the severe disease patient cohort (RR [2.44-46 .01], p = 0.014, Figure 6 ). The heterogeneity between the studies varied substantially ( Table 5) . Publication bias, measured by means of the Egger's test, was only evident in three analyses. However, Egger's test may lack the statistical power to detect bias when the number of studies is small (i.e., fewer than 10) as we only included 4-8 studies.

Seven studies (957 patients) provided disaggregated data for COVID-19 survivors (617 patients, 64 With the exception of a 10-month old neonate, no children were amongst the deaths reported. All pregnant women included in our study survived COVID-19 and associated complications.

A limitation of the current review was that literature search was limited to articles listed in EMBASE, PubMed/ Medline, Scopus, Web of Science, or identified by hand searches. Considering the pace at which the research in this area is moving forward, it is likely that the findings of the publications described in this paper will be quickly complemented by further research. The literature search also excluded grey literature (e.g., preprints, reports, conference proceedings), the importance of which to this topic is unknown, and thus might have introduced another source of search bias. There is also a probability of publication bias, as well as potential for a search bias. Publication bias is likely to result in studies with more positive results being preferentially submitted and accepted for publication.

Moreover, geographical bias cannot be rule out as the majority of the studies (129/ 148) were J o u r n a l P r e -p r o o f conducted in China. While symptoms might be quite comparable across countries, comorbidities, treatments, and outcome potentially depends on the country (and its healthcare system). There is also a considerable risk for a reporting bias towards comorbidities, clinical signs and symptoms, laboratory parameters, imaging features, treatment, outcome, and complications that are present. Specifically, only a minority of studies reported a zero when this information was assessed, but absent in patients.

Lack of data on absent clinical signs and symptoms might lead to distorted estimates of proportion.

Furthermore, the low number of asymptomatic patients must be considered with caution. The metaanalysis of severity and mortality could only be performed with a small number of studies as the minority of the 148 provided data separately for different disease severity groups (e.g., non-severe, severe, survivors, non-survivors). This needs to be considered when interpreting the results, including the publication bias as the Egger's test may lack the statistical power to detect bias when the number of studies is small (i.e., < 10). Lastly, the criteria to classify patients in severe and non-severe COVID-19

disease cohorts varied between studies leading to additional heterogeneity between studies. By virtue of low number of studies available, we could not assess this heterogeneity nor adjust for it.

In conclusion, this unprecedentedly comprehensive systematic review and meta-analysis of the A total of 148 studies were eligible for the literature review and the first part of the meta-analysis (i.e., prevalence). Nineteen studies were included in the second part of the meta-analysis (i.e., severity and mortality). All case studies/ reports were pooled together for visualization (CS_adult, and CS_children [pediatric/neonatal]). The key to the study identifier can be found in Tables 1 (adults) and Table 3 (children). The key to the study identifier can be found in Table 1 (adults), Table 2 (pregnant women), and Table 3 (children). The key to the study identifier can be found in Table 1 . Funnel plots indicate the potential of publication bias. The key to the study identifier can be found in Table 1 . 

Funnel plots indicate the potential of publication bias. The key to the study identifier can be found in Table 1 . 

To assess the sensitivity with respect to studies that only reported a mean and standard deviation, we performed additional probabilistic simulations. Specifically, we assumed that mean and standard deviation were calculated from a skewed normal distribution with unknown shape parameter α (where α=0 corresponds to the standard normal distribution). We then calculated the expectation of the median and the respective IQR under the assumption that α∈(-∞,0], i.e., a left-skewed distribution, and under the assumption that α∈[0,∞), i.e., a right-skewed distribution. Both of these assumptions are the "agnostic" ones in the sense that we consider skewness, but do not assume boundedness. We find the overall median and IQR (of all studies) to be unaffected when including the results of these simulations, indicating that our analyses are stable.

All studies that reported mean and SD (assumption normal distribution)

All studies All studies that reported mean and SD (assumption leftskewed distribution) Supplementary Figure 10 . Proportion of male and female patients in the non-severe, severe, survivors, and non-survivor patient groups. With the exception of the non-survivor with a larger proportion of male patients, the ration male:female patients was 1:1 in all the groups. The key to the study identifier can be found in J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f CS_adult S1 S10 S100 S101 S102 S103 S104 S105 S106 S107 S109 S11 S110 S111 S112 S113 S114 S115 S116 S117 S12 S13 S14 S16 S17 S18_death S18_survival S19

S63_severe S64_adult  S65  S66  S67  S69  S7  S70  S74  S75  S76  S77  S78  S79  S8  S80  S82  S84  S85  S86  S87  S88  S89  S9_nonsevere  S9_severe  S90  S92  S93  S94  S95  S97  S98_imported  S98_secondary S98_tertiary S99 S121_pregnant (n= 1) S120 (n= 9) S123 (n= 1) S119 (n= 1) S126 (n= 1) S122 (n= 1) 0 20 40

Pregnant Women B S133 (n= 2) S138 (n= 8) S130 (n= 731) S137 (n= 1) S139 (n= 1)

S58_pediatric (n= 1)

S6_pediatric (n= 1) S141 (n= 31) S127 (n= 1) S132 (n= 15) S136 (n= 171) S144 (n= 10) S135 (n= 6) S147 (n= 25)

S60_pediatric (n= 4) S143 (n= 20) S128 (n= 1) S64_pediatric (n= 1) S148 (n= 9) S142 (n= 9) S131 (n= 1) S134 (n= 1) S146 (n= 1) S129 (n= 1) S140 (n= 1) S145 (n= 1) S121_pediatric (n= 1) S124_pediatric (n= 1) 0 5 10 15 Median Age [years]

Pediatrics/Neonates C J o u r n a l P r e -p r o o f S10 S100 S101 S103 S105 S106 S107 S108 S109 S11 S110 S111 S112 S114 S115 S117 S12 S15 S16 S18 S19 S2  S21  S25  S28  S30  S31  S32  S34  S36  S37  S38  S39  S4  S40  S41  S42  S43  S45 -no GI  S45 -with GI  S46  S47  S48  S49  S5  S52 - Chronic liver disease Respiratory system disease Heart failure Comorbidities A S1 S10 S100 S101 S103 S105 S106 S107 S108 S109 S11 S110 S111 S112 S113 S114 S115 S116 S117 S12 S13 S14 S15 S16 S17 S18 S19 S2  S20  S21  S22  S23  S24  S25  S26  S27  S28  S29  S3  S30  S31  S33  S34  S35  S36  S37  S38  S39  S4  S40  S41  S42  S43  S44  S45 -no GI  S45 -with GI  S46  S47  S48  S5  S51  S52 - Clinical signs and symptoms B S10 S100 S102 S103 S105 S106 S107 S11 S113 S114 S115 S117 S12 S15 S16 S18 S19 S2  S20  S21  S22  S23  S24  S26  S29  S3  S30  S31  S32  S34  S36  S37  S38  S39  S4  S40  S42  S43  S44  S45 -no GI  S45 -with GI  S46  S47  S48  S5  S50  S52 - Alpha interferon aerosol inhalation S10 S100 S101 S103 S105 S106 S11 S111 S114 S115 S12 S14 S15 S18 S19 S2  S20  S22  S23  S24  S26  S27  S29  S3  S30  S31  S34  S36  S37  S38  S4  S40  S41  S42  S43  S45 -no Survivors C S115 (n=54) S18 (n=109) S107 (n=10) S12 (n=113) S100 (n=32) 

Survivor Study

Heterogeneity: I 2 = 46%, τ 2 = 0.4773, p = 0.12 S115 S107 S100 S18 S67 

Heterogeneity: I 2 = 71%, τ 2 = 0.2661, p = 0.02 S115 S100 S18 S12 S67 

Heterogeneity: I 2 = 68%, τ 2 = 2.3059, p = 0.01 S115 S100 S18 S12 S67 

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Heterogeneity: I 2 = 93%, τ 2 = 1.1147, p < 0.01 S115 S107 S100 S18 S12 S67